The long-term goal of this research is to understand the unique role of proteins encoded by the major histocompatibility complex (MHC) in T cell recognition and activation. The murine cytotoxic T cell (CTL) response to allogeneic class I H-2 molecules is 2 to 3 orders of magnitude greater than the response to xenogeneic class I HLA molecules. This has been shown to reflect structural differences between H-2 and HLA molecules and not expression on cells of different species. Indeed, HLA antigens expressed on murine cells are recognized preferentially as nominal antigens in the context of H-2 molecules. A possible explanation for these observations is that during T cell ontogeny, the T cell repertoire develops to recognize epitopes that closely resemble syngeneic H- 2 molecules. Therefore, CTL recognize allogeneic epitopes more easily than xenogeneic epitopes. Another explanation is that MHC antigens bear conserved determinant(s) that mark them as ligands for T cells. T cells might not interact as well with xenogeneic MHC antigens if such determinants had undergone evolutionary modification. Recognition of such determinants could occur either through the T cell receptor, or through accessory molecules such as CD8. In the proposed work, these possible explanations will be distinguished by the use of transgenic mice expressing either human class I MHC or CD8 molecules or both. The influence of expression of the molecules on: a) The frequency of HLA specific precursors; b) The utilization of HLA antigens as restricting elements; and c) T cell receptor gene usage in HLA-specific responses, will be examined. In addition, the nature of structural differences between HLA and H-2 molecules that are relevant to their recognition by murine T cell will be evaluated by the construction of chimeric HLA/H-2 molecules and determination of their ability to elicit T cell responses. These chimeric molecules will also be used to evaluate the nature of the HLA determinants recognized by H-2 restricted murine CTL. These studies are expected to increase understanding of the role of species-specific structures on MHC antigens, T cell receptors, and/or accessory molecules in T cell recognition and the development of the T cell repertoire. They should also contribute to knowledge concerning the structural features on T cell receptors that mediate antigen recognition, and the nature of processed antigens that become associated with class I MHC products.